This application seeks to identify novel modifiable factors, plasma ceramide and sphingomyelin species, associated with risks of incident heart failure (HF), incident atrial fibrillation (AF), incident sudden cardiac death (SCD) and total mortality. Ceramides and sphingomyelins are cell and circulating lipids that are involved in apoptosis, oxidative stress, ischemia/reperfusion and other mechanisms of relevance to the pathophysiology of HF and arrhythmias. Until recently, all ceramides and sphingomyelins were thought to have similar physiological effects and most studies investigated total levels; however, there is now compelling evidence that species that carry saturated fatty acids of different length exhibit divergent biological activities. These studies provide a strong basis for our hypothesis that higher plasma levels of ceramide and sphingomyelin species that carry the fatty acid 16:0 (16 carbons, 0 double bond) are associated with higher risks of incident HF, AF and SCD, and higher total mortality; and higher plasma levels of ceramide and sphingomyelin species that carry the fatty acids 20:0, 22:0 or 24:0 are associated with lower risks of incident HF, AF and SCD, and lower total mortality. We will investigate these novel hypotheses in the Cardiovascular Health Study (CHS), an NHLBI-funded prospective cohort study of risk factors for cardiovascular disease among older adults. We will measure ceramide and sphingomyelin species in existing plasma samples using liquid chromatography followed by mass spectrometry. Plasma samples collected in 1992 are available on about 3800 CHS participants. We will combine the new data with existing extensive information on risk factors and follow-up data from 1992 to 2011. In Primary Aims, we will investigate the associations of plasma ceramide and sphingomyelin species containing 16:0, 20:0, 22:0, and 24:0 with the risks of incident HF (Aim1), incident AF (Aim 2), incident SCD (Aim 3) and with total and cardiovascular disease mortality (Aim 4). During follow-up, 968 incident HF, 978 incident AF, 200 incident SCD and 2788 deaths have been identified. In Secondary Aims, we will investigate the associations of the ceramide and sphingomyelin species with intermediate endpoints including left ventricular mass from echocardiography, electrocardiographic phenotypes, and markers of left ventricular stress, cardiomyocyte injury and inflammation (Secondary Aim 1); we will also investigate life- style predictors of levels of the ceramide and sphingomyelin species, including medications, dietary factors, smoking and physical activity measured before the 1992 exam (Secondary Aim 2). This study will comprehensively examine the associations of novel modifiable molecules, ceramide and sphingomyelin species, with incidence and mediators of HF and arrhythmia, mortality, and life-style characteristics. Little is known about potential divergent effects of distinct ceramde and sphingomyelin species in humans. The study will inform novel drug targets and novel prevention efforts in the fight against HF and arrhythmia.